Combination of a pd-1 antagonist and a vegfr inhibitor for treating cancer

ABSTRACT

The present disclosure describes combination therapies comprising an antagonist of Programmed Death 1 receptor (PD-1) and a VEGFR inhibitor, and the use of the combination therapies for the treatment of cancer, and in particular for treating cancers that express PD-L1.

RELATED APPLICATIONS

This application claims the benefit of U.S. provisional application61/935,809, filed on Feb. 4, 2014, which is incorporated by reference inits entirety.

SEQUENCE LISTING

The instant application contains a Sequence Listing which has beensubmitted electronically in ASCII format and is hereby incorporated byreference in its entirety. Said ASCII copy, created on Jan. 29, 2015, isnamed PCFC-956-WO1_SL.txt and is 32,535 bytes in size.

FIELD OF THE INVENTION

The present invention relates to combination therapies useful for thetreatment of cancer. In particular, the invention relates to acombination therapy which comprises an antagonist of a Programmed Death1 protein (PD-1) and an inhibitor of the vascular endothelial growthfactor receptor (VEGFR) pathway.

BACKGROUND OF THE INVENTION

PD-1 is recognized as an important player in immune regulation and themaintenance of peripheral tolerance. PD-1 is moderately expressed onnaive T, B and NKT cells and up-regulated by T/B cell receptor signalingon lymphocytes, monocytes and myeloid cells (1).

Two known ligands for PD-1, PD-L1 (B7-H1) and PD-L2 (B7-DC), areexpressed in human cancers arising in various tissues. In large samplesets of e.g. ovarian, renal, colorectal, pancreatic, liver cancers andmelanoma, it was shown that PD-L1 expression correlated with poorprognosis and reduced overall survival irrespective of subsequenttreatment (2-13). Similarly, PD-1 expression on tumor infiltratinglymphocytes was found to mark dysfunctional T cells in breast cancer andmelanoma (14-15) and to correlate with poor prognosis in renal cancer(16). Thus, it has been proposed that PD-L1 expressing tumor cellsinteract with PD-1 expressing T cells to attenuate T cell activation andevasion of immune surveillance, thereby contributing to an impairedimmune response against the tumor.

Several monoclonal antibodies that inhibit the interaction between PD-1and one or both of its ligands PD-L1 and PD-L2 are in clinicaldevelopment for treating cancer. It has been proposed that the efficacyof such antibodies might be enhanced if administered in combination withother approved or experimental cancer therapies, e.g., radiation,surgery, chemotherapeutic agents, targeted therapies, agents thatinhibit other signaling pathways that are disregulated in tumors, andother immune enhancing agents.

Protein tyrosine kinases have been identified as crucial targets in thetherapeutic treatment of cancer. Growth factor ligands and theirrespective receptor tyrosine kinases are required for tumor angiogenesisand growth. Vascular endothelial growth factor (VEGF) is a criticalcomponent in the process leading to the branching, extension, andsurvival of endothelial cells forming new blood vessels duringangiogenesis. Unwanted angiogenesis is a hallmark of several diseases,such as retinopathies, psoriasis, rheumatoid arthritis, age-relatedmacular degeneration (AMD), and cancer (including solid tumors) Folkman,Nature Med., 1, 27-31 (1995).

Vascular endothelial growth factor receptor (VEGFR) inhibitors have beenapproved for the treatment of various types of cancer, includingadvanced and metastatic renal-cell carcinoma, gastrointestinal stromaltumors and hepatocellular carcinoma, and continue to be investigated inthe clinical setting. It has been proposed that the efficacy of suchinhibitors might be enhanced if administered in combination with otherapproved or experimental cancer therapies, e.g., radiation, surgery,chemotherapeutic agents, targeted therapies, agents that inhibit othersignaling pathways that are disregulated in tumors, and other immuneenhancing agents.

SUMMARY OF THE INVENTION

In one embodiment, the invention provides a method for treating a cancerin an individual comprising administering to the individual acombination therapy which comprises a PD-1 antagonist and a VEGFRinhibitor.

In another embodiment, the invention provides a medicament comprising aPD-1 antagonist for use in combination with a VEGFR inhibitor fortreating a cancer.

In yet another embodiment, the invention provides a medicamentcomprising a VEGFR inhibitor for use in combination with a PD-1antagonist for treating a cancer.

Other embodiments provide use of a PD-1 antagonist in the manufacture ofmedicament for treating a cancer in an individual when administered incombination with a VEGFR inhibitor and use of a VEGFR inhibitor in themanufacture of a medicament for treating a cancer in an individual whenadministered in combination with a PD-1 antagonist.

In a still further embodiment, the invention provides use of a PD-1antagonist and a VEGFR inhibitor in the manufacture of medicaments fortreating a cancer in an individual. In some embodiments, the medicamentscomprise a kit, and the kit also comprises a package insert comprisinginstructions for using the PD-1 antagonist in combination with a VEGFRinhibitor to treat a cancer in an individual.

In all of the above treatment method, medicaments and uses, the PD-1antagonist inhibits the binding of PD-L1 to PD-1, and preferably alsoinhibits the binding of PD-L2 to PD-1. In some embodiments of the abovetreatment method, medicaments and uses, the PD-1 antagonist is amonoclonal antibody, or an antigen binding fragment thereof, whichspecifically binds to PD- or to PD-L1 and blocks the binding of PD-L1 toPD-1. In one embodiment, the PD-1 antagonist is an anti-PD-1 antibodywhich comprises a heavy chain and a light chain, and wherein the heavyand light chains comprise the amino acid sequences shown in FIG. 6 (SEQID NO:21 and SEQ ID NO:22).

In all of the above embodiments of the treatment method, medicaments anduses herein, the VEGFR inhibitor isN-methyl-2-[3-((E)-2-pyridin-2-yl-vinyl)-1H-indazol-6-ylsulfanyl]-benzamideor a pharmaceutically acceptable salt thereof.

In some embodiments of the above treatment method, medicaments and usesof the invention, the individual is a human and the cancer is a solidtumor and in some embodiments, the solid tumor is bladder cancer, breastcancer, clear cell kidney cancer, head/neck squamous cell carcinoma,lung squamous cell carcinoma, malignant melanoma, non-small-cell lungcancer (NSCLC), ovarian cancer, pancreatic cancer, prostate cancer,renal cell cancer, small-cell lung cancer (SCLC) or triple negativebreast cancer. In some embodiments, the cancer is renal cell carcinoma(RCC). In some embodiments, the cancer is clear cell kidney cancer.

In other embodiments of the above treatment method, medicaments and usesof the invention, the individual is a human and the cancer is a Hememalignancy and in some embodiments, the Heme malignancy is acutelymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chroniclymphocytic leukemia (CLL), chronic myeloid leukemia (CML), diffuselarge B-cell lymphoma (DLBCL), EBV-positive DLBCL, primary mediastinallarge B-cell lymphoma, T-cell/histiocyte-rich large B-cell lymphoma,follicular lymphoma. Hodgkin's lymphoma (HL), mantle cell lymphoma(MCL), multiple myeloma (MM), myeloid cell leukemia-1 protein (Mcl-1),myelodysplastic syndrome (MDS), non-Hodgkin's lymphoma (NHL), or smalllymphocytic lymphoma (SLL).

Also, in some embodiments of any of the above treatment method,medicaments and uses, the cancer tests positive for the expression ofone or both of PD-L1 and PD-L2. In still other embodiments, the cancerhas elevated PD-L1 expression.

In one embodiment of the above treatment method, medicaments and uses,the individual is a human and the cancer is RCC that tests positive forhuman PD-L1.

In another embodiment of the above treatment method, medicaments anduses, the cancer is advanced RCC with clear cell subtype and is presentin a human who has not been previously treated for RCC.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows amino acid sequences of the light chain and heavy chainCDRs for an exemplary anti-PD-1 monoclonal antibody useful in thepresent invention (SEQ ID NOs: 1-6).

FIG. 2 shows amino acid sequences of the light chain and heavy chainCDRs for another exemplary anti-PD-1 monoclonal antibody useful in thepresent invention (SEQ ID NOs:7-12).

FIG. 3 shows amino acid sequences of the heavy chain variable region andfull length heavy chain for an exemplary anti-PD-1 monoclonal antibodyuseful in the present invention (SEQ ID NO:13 and SEQ ID NO:14).

FIG. 4 shows amino acid sequences of alternative light chain variableregions for an exemplary anti-PD-1 monoclonal antibody useful in thepresent invention (SEQ ID NOs: 15-17).

FIGS. 5A-5B show amino acid sequences of alternative light chains for anexemplary anti-PD-1 monoclonal antibody useful in the present invention,with FIG. 5A showing the amino acid sequences for the K09A-L-11 andK09A-L-16 light chains (SEQ ID NOs: 18 and 19, respectively) and FIG. 5Bshowing the amino acid sequence for the K09A-L-17 light chain (SEQ IDNO:20).

FIG. 6 shows amino acid sequences of the heavy and light chains forMK-3475 (SEQ ID NOs. 21 and 22, respectively).

FIG. 7 shows amino acid sequences of the heavy and light chains fornivolumab (SEQ ID NOs. 23 and 24, respectively).

DETAILED DESCRIPTION Abbreviations

Throughout the detailed description and examples of the invention thefollowing abbreviations will be used:

BID One dose twice daily

CDR Complementarity determining region

CHO Chinese hamster ovary

DFS Disease free survival

DTR Dose limiting toxicity

FFPE formalin-fixed, paraffin-embedded

FR Framework region

IgG Immunoglobulin G

IHC Immunohistochemistry or immunohistochemical

MTD Maximum tolerated dose

NCBI National Center for Biotechnology Information

NCI National Cancer Institute

OR Overall response

OS Overall survival

PD Progressive disease

PFS Progression free survival

PR Partial response

Q2W One dose every two weeks

Q3W One dose every three weeks

QD One dose per day

RECIST Response Evaluation Criteria in Solid Tumors

SD Stable disease

VH Immunoglobulin heavy chain variable region

VK Immunoglobulin kappa light chain variable region

I. DEFINITIONS

So that the invention may be more readily understood, certain technicaland scientific terms are specifically defined below. Unless specificallydefined elsewhere in this document, all other technical and scientificterms used herein have the meaning commonly understood by one ofordinary skill in the art to which this invention belongs.

“About” when used to modify a numerically defined parameter (e.g., thedose of a PD-1 antagonist or VEGFR inhibitor, or the length of treatmenttime with a combination therapy described herein) means that theparameter may vary by as much as 10% below or above the stated numericalvalue for that parameter. For example, a dose of about 5 mg/kg may varybetween 4.5 mg/kg and 5.5 mg/kg.

As used herein, including the appended claims, the singular forms ofwords such as “a,” “an,” and “the,” include their corresponding pluralreferences unless the context clearly dictates otherwise.

“Administration” and “treatment,” as it applies to an animal, human,experimental subject, cell, tissue, organ, or biological fluid, refersto contact of an exogenous pharmaceutical, therapeutic, diagnosticagent, or composition to the animal, human, subject, cell, tissue,organ, or biological fluid. Treatment of a cell encompasses contact of areagent to the cell, as well as contact of a reagent to a fluid, wherethe fluid is in contact with the cell. “Administration” and “treatment”also means in vitro and ex vivo treatments, e.g., of a cell, by areagent, diagnostic, binding compound, or by another cell. The term“subject” includes any organism, preferably an animal, more preferably amammal (e.g., rat, mouse, dog, cat, rabbit) and most preferably a human.

As used herein, the term “antibody” refers to any form of antibody thatexhibits the desired biological or binding activity. Thus, it is used inthe broadest sense and specifically covers, but is not limited to,monoclonal antibodies (including full length monoclonal antibodies),polyclonal antibodies, multispecific antibodies (e.g., bispecificantibodies), humanized, fully human antibodies, chimeric antibodies andcamelized single domain antibodies. “Parental antibodies” are antibodiesobtained by exposure of an immune system to an antigen prior tomodification of the antibodies for an intended use, such as humanizationof an antibody for use as a human therapeutic.

In general, the basic antibody structural unit comprises a tetramer.Each tetramer includes two identical pairs of polypeptide chains, eachpair having one “light” (about 25 kDa) and one “heavy” chain (about50-70 kDa). The amino-terminal portion of each chain includes a variableregion of about 100 to 110 or more amino acids primarily responsible forantigen recognition. The carboxy-terminal portion of the heavy chain maydefine a constant region primarily responsible for effector function.Typically, human light chains are classified as kappa and lambda lightchains. Furthermore, human heavy chains are typically classified as mu,delta, gamma, alpha, or epsilon, and define the antibody's isotype asIgM, IgD, IgG, IgA, and IgE, respectively. Within light and heavychains, the variable and constant regions are joined by a “J” region ofabout 12 or more amino acids, with the heavy chain also including a “D”region of about 10 more amino acids. See generally, FundamentalImmunology Ch. 7 (Paul, W., ed., 2nd ed. Raven Press, N.Y. (1989).

The variable regions of each light/heavy chain pair form the antibodybinding site. Thus, in general, an intact antibody has two bindingsites. Except in bifunctional or bispecific antibodies, the two bindingsites are, in general, the same.

Typically, the variable domains of both the heavy and light chainscomprise three hypervariable regions, also called complementaritydetermining regions (CDRs), which are located within relativelyconserved framework regions (FR). The CDRs are usually aligned by theframework regions, enabling binding to a specific epitope. In general,from N-terminal to C-terminal, both light and heavy chains variabledomains comprise FR1, CDR1, FR2, CDR2, FR3. CDR3 and FR4. The assignmentof amino acids to each domain is, generally, in accordance with thedefinitions of Sequences of Proteins of Immunological Interest, Kabat,et al.; National Institutes of Health, Bethesda, Md.; 5^(th) ed.; NIHPubl. No. 91-3242 (1991); Kabat (1978) Adv. Prot. Chem. 32:1-75; Kabat,et al., (1977) J. Biol. Chem. 252:6609-6616; Chothia, et al., (1987) JMol. Biol. 196:901-917 or Chothia, et al., (1989) Nature 342:878-883.

As used herein, the term “hypervariable region” refers to the amino acidresidues of an antibody that are responsible for antigen-binding. Thehypervariable region comprises amino acid residues from a“complementarity determining region” or “CDR” (i.e. CDRL1, CDRL2 andCDRL3 in the light chain variable domain and CDRH1, CDRH2 and CDRH3 inthe heavy chain variable domain). See Kabat et al. (1991) Sequences ofProteins of Immunological Interest, 5th Ed. Public Health Service,National Institutes of Health, Bethesda, Md. (defining the CDR regionsof an antibody by sequence); see also Chothia and Lesk (1987) J. Mol.Biol. 196: 901-917 (defining the CDR regions of an antibody bystructure). As used herein, the term “framework” or “FR” residues refersto those variable domain residues other than the hypervariable regionresidues defined herein as CDR residues.

As used herein, unless otherwise indicated, “antibody fragment” or“antigen binding fragment” refers to antigen binding fragments ofantibodies, i.e. antibody fragments that retain the ability to bindspecifically to the antigen bound by the full-length antibody, e.g.fragments that retain one or more CDR regions. Examples of antibodybinding fragments include, but are not limited to, Fab, Fab′, F(ab′)₂,and Fv fragments; diabodies; linear antibodies; single-chain antibodymolecules, e.g., sc-Fv; nanobodies and multispecific antibodies formedfrom antibody fragments.

An antibody that “specifically binds to” a specified target protein isan antibody that exhibits preferential binding to that target ascompared to other proteins, but this specificity does not requireabsolute binding specificity. An antibody is considered “specific” forits intended target if its binding is determinative of the presence ofthe target protein in a sample, e.g. without producing undesired resultssuch as false positives. Antibodies, or binding fragments thereof,useful in the present invention will bind to the target protein with anaffinity that is at least two fold greater, preferably at least tentimes greater, more preferably at least 20-times greater, and mostpreferably at least 100-times greater than the affinity with non-targetproteins. As used herein, an antibody is said to bind specifically to apolypeptide comprising a given amino acid sequence, e.g. the amino acidsequence of a mature human PD-1 or human PD-L1 molecule, if it binds topolypeptides comprising that sequence but does not bind to proteinslacking that sequence.

“Chimeric antibody” refers to an antibody in which a portion of theheavy and/or light chain is identical with or homologous tocorresponding sequences in an antibody derived from a particular species(e.g., human) or belonging to a particular antibody class or subclass,while the remainder of the chain(s) is identical with or homologous tocorresponding sequences in an antibody derived from another species(e.g., mouse) or belonging to another antibody class or subclass, aswell as fragments of such antibodies, so long as they exhibit thedesired biological activity.

“Human antibody” refers to an antibody that comprises humanimmunoglobulin protein sequences only. A human antibody may containmurine carbohydrate chains if produced in a mouse, in a mouse cell, orin a hybridoma derived from a mouse cell. Similarly, “mouse antibody” or“rat antibody” refer to an antibody that comprises only mouse or ratimmunoglobulin sequences, respectively.

“Humanized antibody” refers to forms of antibodies that containsequences from non-human (e.g., murine) antibodies as well as humanantibodies. Such antibodies contain minimal sequence derived fromnon-human immunoglobulin. In general, the humanized antibody willcomprise substantially all of at least one, and typically two, variabledomains, in which all or substantially all of the hypervariable loopscorrespond to those of a non-human immunoglobulin and all orsubstantially all of the FR regions are those of a human immunoglobulinsequence. The humanized antibody optionally also will comprise at leasta portion of an immunoglobulin constant region (Fc), typically that of ahuman immunoglobulin. The prefix “hum”. “hu” or “h” is added to antibodyclone designations when necessary to distinguish humanized antibodiesfrom parental rodent antibodies. The humanized forms of rodentantibodies will generally comprise the same CDR sequences of theparental rodent antibodies, although certain amino acid substitutionsmay be included to increase affinity, increase stability of thehumanized antibody, or for other reasons.

The terms “cancer”, “cancerous”, or “malignant” refer to or describe thephysiological condition in mammals that is typically characterized byunregulated cell growth. Examples of cancer include but are not limitedto, carcinoma, lymphoma, leukemia, blastoma, and sarcoma. Moreparticular examples of such cancers include squamous cell carcinoma,myeloma, small-cell lung cancer, non-small cell lung cancer, glioma,hodgkin's lymphoma, non-hodgkin's lymphoma, acute myeloid leukemia(AML), multiple myeloma, gastrointestinal (tract) cancer, renal cancer,ovarian cancer, liver cancer, lymphoblastic leukemia, lymphocyticleukemia, colorectal cancer, endometrial cancer, kidney cancer, prostatecancer, thyroid cancer, melanoma, chondrosarcoma, neuroblastoma,pancreatic cancer, glioblastoma multiforme, cervical cancer, braincancer, stomach cancer, bladder cancer, hepatoma, breast cancer, coloncarcinoma, and head and neck cancer. Another particular example ofcancer includes renal cell carcinoma. A further particular example ofcancer includes clear cell kidney cancer. Cancers that may be treated inaccordance with the present invention include those characterized byelevated expression of one or both of PD-L1 and PD-L2 in tested tissuesamples.

“Biotherapeutic agent” means a biological molecule, such as an antibodyor fusion protein, that blocks ligand/receptor signaling in anybiological pathway that supports tumor maintenance and/or growth orsuppresses the anti-tumor immune response.

“CDR” or “CDRs” as used herein means complementarity determiningregion(s) in a immunoglobulin variable region, defined using the Kabatnumbering system, unless otherwise indicated.

“Chemotherapeutic agent” is a chemical compound useful in the treatmentof cancer. Classes of chemotherapeutic agents include, but are notlimited to: alkylating agents, antimetabolites, kinase inhibitors,spindle poison plant alkaloids, cytoxic/antitumor antibiotics,topisomerase inhibitors, photosensitizers, anti-estrogens and selectiveestrogen receptor modulators (SERMs), anti-progesterones, estrogenreceptor down-regulators (ERDs), estrogen receptor antagonists,leutinizing hormone-releasing hormone agonists, anti-androgens,aromatase inhibitors, EGFR inhibitors, VEGF inhibitors, and anti-senseoligonucleotides that inhibit expression of genes implicated in abnormalcell proliferation or tumor growth. Chemotherapeutic agents useful inthe treatment methods of the present invention include cytostatic and/orcytotoxic agents.

“Chothia” as used herein means an antibody numbering system described inAl-Lazikani et al., JMB 273:927-948 (1997).

“Conservatively modified variants” or “conservative substitution” refersto substitutions of amino acids in a protein with other amino acidshaving similar characteristics (e.g. charge, side-chain size,hydrophobicity/hydrophilicity, backbone conformation and rigidity,etc.), such that the changes can frequently be made without altering thebiological activity or other desired property of the protein, such asantigen affinity and/or specificity. Those of skill in this artrecognize that, in general, single amino acid substitutions innon-essential regions of a polypeptide do not substantially alterbiological activity (see, e.g., Watson et al. (1987) Molecular Biologyof the Gene, The Benjamin/Cummings Pub. Co., p. 224 (4th Ed.)). Inaddition, substitutions of structurally or functionally similar aminoacids are less likely to disrupt biological activity. Exemplaryconservative substitutions are set forth in Table 1 below.

TABLE 1 Exemplary Conservative Amino Acid Substitutions Original residueConservative substitution Ala (A) Gly; Ser Arg (R) Lys; His Asn (N) Gln;His Asp (D) Glu; Asn Cys (C) Ser; Ala Gln (Q) Asn Glu (E) Asp; Gln Gly(G) Ala His (H) Asn; Gln Ile (I) Leu; Val Leu (L) Ile; Val Lys (K) Arg;His Met (M) Leu; Ile; Tyr Phe (F) Tyr; Met; Leu Pro (P) Ala Ser (S) ThrThr (T) Ser Trp (W) Tyr; Phe Tyr (Y) Trp; Phe Val (V) Ile; Leu

“Consists essentially of,” and variations such as “consist essentiallyof” or “consisting essentially of,” as used throughout the specificationand claims, indicate the inclusion of any recited elements or group ofelements, and the optional inclusion of other elements, of similar ordifferent nature than the recited elements, that do not materiallychange the basic or novel properties of the specified dosage regimen,method, or composition. As a non-limiting example, a PD-1 antagonistthat consists essentially of a recited amino acid sequence may alsoinclude one or more amino acids, including substitutions of one or moreamino acid residues, which do not materially affect the properties ofthe binding compound.

“Diagnostic anti-PD-L monoclonal antibody” means a mAb whichspecifically binds to the mature form of the designated PD-L (PD-L1 orPDL2) that is expressed on the surface of certain mammalian cells. Amature PD-L lacks the presecretory leader sequence, also referred to asleader peptide The terms “PD-L” and “mature PD-L” are usedinterchangeably herein, and shall be understood to mean the samemolecule unless otherwise indicated or readily apparent from thecontext.

As used herein, a diagnostic anti-human PD-L mAb or an anti-hPD-L1 mAbrefers to a monoclonal antibody that specifically binds to mature humanPD-L1. A mature human PD-L1 molecule consists of amino acids 19-290 ofthe following sequence:

(SEQ ID NO: 25) MRIFAVFIFMTYWHLLNAFTVTVPKDLYVVEYGSNMTIECKFPVEKQLDLAALIVYWEMEDKNIIQFVHGEEDLKVQHSSYRQRARLLKDQLSLGNAALQITDVKLQDAGVYRCMISYGGADYKRITVKVNAPYNKINQRILVVDPVTSEHELTCQAEGYPKAEVIWTSSDHQVLSGKTTTTNSKREEKLFNVTSTLRINTTTNEIFYCTFRRLDPEENHTAELVIPELPLAHPPNERTHLVILGAILLCLGVALTFIFRLRKGRMMDVKKCGIQDTNSKKQ SDTHLEET.

Specific examples of diagnostic anti-human PD-L1 mAbs useful asdiagnostic mAbs for immunohistochemistry (IHC) detection of PD-Lexpression in formalin-fixed, paraffin-embedded (FFPE) tumor tissuesections are antibody 20C3 and antibody 22C3, which are described in thecopending international patent application PCT/US13/075932, filed 18Dec. 2013 and published as WO2014/100079 on 26 Jun. 2014. Anotheranti-human PD-L1 mAb that has been reported to be useful for IHCdetection of PD-L1 expression in FFPE tissue sections (Chen, B. J. etal., Clin Cancer Res 19: 3462-3473 (2013)) is a rabbit anti-human PD-L1mAb publicly available from Sino Biological, Inc. (Beijing, P.R. China;Catalog number 10084-R015).

“Framework region” or “FR” as used herein means the immunoglobulinvariable regions excluding the CDR regions.

“Homology” refers to sequence similarity between two polypeptidesequences when they are optimally aligned. When a position in both ofthe two compared sequences is occupied by the same amino acid monomersubunit, e.g., if a position in a light chain CDR of two different Absis occupied by alanine, then the two Abs are homologous at thatposition. The percent of homology is the number of homologous positionsshared by the two sequences divided by the total number of positionscompared×100. For example, if 8 of 10 of the positions in two sequencesare matched or homologous when the sequences are optimally aligned thenthe two sequences are 80% homologous. Generally, the comparison is madewhen two sequences are aligned to give maximum percent homology. Forexample, the comparison can be performed by a BLAST algorithm whereinthe parameters of the algorithm are selected to give the largest matchbetween the respective sequences over the entire length of therespective reference sequences.

The following references relate to BLAST algorithms often used forsequence analysis: BLAST ALGORITHMS: Altschul, S. F., et al., (1990) J.Mol. Biol. 215:403-410; Gish, W., et al., (1993) Nature Genet.3:266-272; Madden, T. L., et al., (1996) Meth. Enzymol. 266:131-141;Altschul, S. F., et al., (1997) Nucleic Acids Res. 25:3389-3402; Zhang,J., et al., (1997) Genome Res. 7:649-656; Wootton, J. C., et al., (1993)Comput. Chem. 17:149-163; Hancock, J. M. et al., (1994) Comput. Appl.Biosci. 10:67-70; ALIGNMENT SCORING SYSTEMS: Dayhoff, M. O., et al., “Amodel of evolutionary change in proteins.” in Atlas of Protein Sequenceand Structure, (1978) vol. 5, suppl. 3. M. O. Dayhoff (ed.), pp.345-352, Natl. Biomed. Res. Found., Washington, D.C.; Schwartz, R. M.,et al., “Matrices for detecting distant relationships.” in Atlas ofProtein Sequence and Structure, (1978) vol. 5, suppl. 3.” M. O. Dayhoff(ed.), pp. 353-358, Natl. Biomed. Res. Found., Washington, D.C.;Altschul, S. F., (1991) J. Mol. Biol. 219:555-565; States, D. J., etal., (1991) Methods 3:66-70; Henikoff, S., et al., (1992) Proc. Natl.Acad. Sci. USA 89:10915-10919; Altschul, S. F., et al., (1993) J. Mol.Evol. 36:290-300; ALIGNMENT STATISTICS: Karlin, S., et al., (1990) Proc.Natl. Acad. Sci. USA 87:2264-2268; Karlin, S., et al., (1993) Proc.Natl. Acad. Sci. USA 90:5873-5877; Dembo, A., et al., (1994) Ann. Prob.22:2022-2039; and Altschul, S. F. “Evaluating the statisticalsignificance of multiple distinct local alignments.” in Theoretical andComputational Methods in Genome Research (S. Suhai, ed.), (1997) pp.1-14, Plenum, N.Y.

“Isolated antibody” and “isolated antibody fragment” refers to thepurification status and in such context means the named molecule issubstantially free of other biological molecules such as nucleic acids,proteins, lipids, carbohydrates, or other material such as cellulardebris and growth media. Generally, the term “isolated” is not intendedto refer to a complete absence of such material or to an absence ofwater, buffers, or salts, unless they are present in amounts thatsubstantially interfere with experimental or therapeutic use of thebinding compound as described herein.

“Kabat” as used herein means an immunoglobulin alignment and numberingsystem pioneered by Elvin A. Kabat ((1991) Sequences of Proteins ofImmunological Interest, 5th Ed. Public Health Service, NationalInstitutes of Health, Bethesda, Md.).

“Monoclonal antibody” or “mAb” or “Mab”, as used herein, refers to apopulation of substantially homogeneous antibodies, i.e., the antibodymolecules comprising the population are identical in amino acid sequenceexcept for possible naturally occurring mutations that may be present inminor amounts. In contrast, conventional (polyclonal) antibodypreparations typically include a multitude of different antibodieshaving different amino acid sequences in their variable domains,particularly their CDRs, which are often specific for differentepitopes. The modifier “monoclonal” indicates the character of theantibody as being obtained from a substantially homogeneous populationof antibodies, and is not to be construed as requiring production of theantibody by any particular method. For example, the monoclonalantibodies to be used in accordance with the present invention may bemade by the hybridoma method first described by Kohler et al. (1975)Nature 256: 495, or may be made by recombinant DNA methods (see, e.g.,U.S. Pat. No. 4,816,567). The “monoclonal antibodies” may also beisolated from phage antibody libraries using the techniques described inClackson et al. (1991) Nature 352: 624-628 and Marks et al. (1991) J.Mol. Biol. 222: 581-597, for example. See also Presta (2005) J. AllergyClin. Immunol. 116:731.

“Patient” or “subject” refers to any single subject for which therapy isdesired or that is participating in a clinical trial, epidemiologicalstudy or used as a control, including humans and mammalian veterinarypatients such as cattle, horses, dogs, and cats.

“PD-1 antagonist” means any chemical compound or biological moleculethat blocks binding of PD-L1 expressed on a cancer cell to PD-1expressed on an immune cell (T cell, B cell or NKT cell) and preferablyalso blocks binding of PD-L2 expressed on a cancer cell to theimmune-cell expressed PD-1. Alternative names or synonyms for PD-1 andits ligands include: PDCD1, PD1, CD279 and SLEB2 for PD-1; PDCD1L1,PDL1, B7H1, B7-4, CD274 and B7-H for PD-L1; and PDCD1L2, PDL2, B7-DC,Btdc and CD273 for PD-L2. In any of the treatment method, medicamentsand uses of the present invention in which a human individual is beingtreated, the PD-1 antagonist blocks binding of human PD-L1 to humanPD-1, and preferably blocks binding of both human PD-L and PD-L2 tohuman PD-1. Human PD-1 amino acid sequences can be found in NCBI LocusNo.: NP_005009. Human PD-L1 and PD-L2 amino acid sequences can be foundin NCBI Locus No.: NP_054862 and NP_079515, respectively.

PD-1 antagonists useful in the any of the treatment method, medicamentsand uses of the present invention include a monoclonal antibody (mAb),or antigen binding fragment thereof, which specifically binds to PD-1 orPD-L1, and preferably specifically binds to human PD-1 or human PD-L1.The mAb may be a human antibody, a humanized antibody or a chimericantibody, and may include a human constant region. In some embodimentsthe human constant region is selected from the group consisting of IgG1,IgG2, IgG3 and IgG4 constant regions, and in preferred embodiments, thehuman constant region is an IgG1 or IgG4 constant region. In someembodiments, the antigen binding fragment is selected from the groupconsisting of Fab, Fab′-SH, F(ab′)₂, scFv and Fv fragments.

Examples of mAbs that bind to human PD-1, and useful in the treatmentmethod, medicaments and uses of the present invention, are described inU.S. Pat. No. 7,488,802, U.S. Pat. No. 7,521,051, U.S. Pat. No.8,008,449, U.S. Pat. No. 8,354,509, U.S. Pat. No. 8,168,757,WO2004/004771, WO2004/072286, WO2004/056875, and US2011/0271358.Specific anti-human PD-1 mAbs useful as the PD-1 antagonist in thetreatment method, medicaments and uses of the present invention include:MK-3475, a humanized IgG4 mAb with the structure described in WHO DrugInformation, Vol. 27, No. 2, pages 161-162 (2013) and which comprisesthe heavy and light chain amino acid sequences shown in FIG. 6,nivolumab (BMS-936558), a human IgG4 mAb with the structure described inWHO Drug Information, Vol. 27, No. 1, pages 68-69 (2013) and whichcomprises the heavy and light chain amino acid sequences shown in FIG.7; the humanized antibodies h409A11, h409A16 and h409A17, which aredescribed in WO2008/156712, and AMP-514, which is being developed byMedImmune.

Examples of mAbs that bind to human PD-L1, and useful in the treatmentmethod, medicaments and uses of the present invention, are described inWO2013/019906, WO2010/077634 A1 and U.S. Pat. No. 8,383,796. Specificanti-human PD-L1 mAbs useful as the PD-1 antagonist in the treatmentmethod, medicaments and uses of the present invention include MPDL3280A,BMS-936559, MED14736, MSB0010718C and an antibody which comprises theheavy chain and light chain variable regions of SEQ ID NO:24 and SEQ IDNO:21, respectively, of WO2013/019906.

Other PD-1 antagonists useful in the any of the treatment method,medicaments and uses of the present invention include an immunoadhesinthat specifically binds to PD-1 or PD-L1, and preferably specificallybinds to human PD-1 or human PD-L1, e.g., a fusion protein containingthe extracellular or PD-1 binding portion of PD-L1 or PD-L2 fused to aconstant region such as an Fc region of an immunoglobulin molecule.Examples of immunoadhesion molecules that specifically bind to PD-1 aredescribed in WO2010/027827 and WO2011/066342. Specific fusion proteinsuseful as the PD-1 antagonist in the treatment method, medicaments anduses of the present invention include AMP-224 (also known as B7-DCIg),which is a PD-L2-FC fusion protein and binds to human PD-1.

In some preferred embodiments of the treatment method, medicaments anduses of the present invention, the PD-1 antagonist is a monoclonalantibody, or antigen binding fragment thereof, which comprises: (a)light chain CDRs SEQ ID NOs: 1, 2 and 3 and heavy chain CDRs SEQ ID NOs:4, 5 and 6; or (b) light chain CDRs SEQ ID NOs: 7, 8 and 9 and heavychain CDRs SEQ ID NOs: 10, 11 and 12.

In other preferred embodiments of the treatment method, medicaments anduses of the present invention, the PD-1 antagonist is a monoclonalantibody, or antigen binding fragment thereof, which specifically bindsto human PD-1 and comprises (a) a heavy chain variable region comprisingSEQ ID NO: 13 or a variant thereof, and (b) a light chain variableregion comprising an amino acid sequence selected from the groupconsisting of SEQ ID NO:15 or a variant thereof; SEQ ID NO:16 or avariant thereof; and SEQ ID NO: 17 or a variant thereof. A variant of aheavy chain variable region sequence is identical to the referencesequence except having up to 17 conservative amino acid substitutions inthe framework region (i.e., outside of the CDRs), and preferably hasless than ten, nine, eight, seven, six or five conservative amino acidsubstitutions in the framework region. A variant of a light chainvariable region sequence is identical to the reference sequence excepthaving up to five conservative amino acid substitutions in the frameworkregion (i.e., outside of the CDRs), and preferably has less than four,three or two conservative amino acid substitution in the frameworkregion.

In another preferred embodiment of the treatment method, medicaments anduses of the present invention, the PD-1 antagonist is a monoclonalantibody which specifically binds to human PD-1 and comprises (a) aheavy chain comprising SEQ ID NO: 14 and (b) a light chain comprisingSEQ ID NO:18, SEQ ID NO:19 or SEQ ID NO:20.

In yet another preferred embodiment of the treatment method, medicamentsand uses of the present invention, the PD-1 antagonist is a monoclonalantibody which specifically binds to human PD-1 and comprises (a) aheavy chain comprising SEQ ID NO: 14 and (b) a light chain comprisingSEQ ID NO: 18.

Table 2 below provides a list of the amino acid sequences of exemplaryanti-PD-1 mAbs for use in the treatment method, medicaments and uses ofthe present invention, and the sequences are shown in FIGS. 1-5.

TABLE 2 EXEMPLARY ANTI-HUMAN PD-1 MONOCLONAL ANTIBODIES A. Compriseslight and heavy chain CDRs of hPD-1.08A in WO2008/156712 CDRL1 SEQ IDNO: 1 CDRL2 SEQ ID NO: 2 CDRL3 SEQ ID NO: 3 CDRH1 SEQ ID NO: 4 CDRH2 SEQID NO: 5 CDRH3 SEQ ID NO: 6 B. Comprises light and heavy chain CDRs ofhPD-1.09A in WO2008/156712 CDRL1 SEQ ID NO: 7 CDRL2 SEQ ID NO: 8 CDRL3SEQ ID NO: 9 CDRH1 SEQ ID NO: 10 CDRH2 SEQ ID NO: 11 CDRH3 SEQ ID NO: 12C. Comprises the mature h109A heavy chain variable region and one of themature K09A light chain variable regions in WO2008/156712 Heavy chain VRSEQ ID NO: 13 Light chain VR SEQ ID NO: 15 or SEQ ID NO: 16 or SEQ IDNO: 17 D. Comprises the mature 409 heavy chain and one of the matureK09A light chains in WO2008/156712 Heavy chain SEQ ID NO: 14 Light chainSEQ ID NO: 18 or SEQ ID NO: 19 or SEQ ID NO: 20

“PD-L1” or “PD-L2” expression as used herein means any detectable levelof expression of the designated PD-L protein on the cell surface or ofthe designated PD-L mRNA within a cell or tissue. PD-L proteinexpression may be detected with a diagnostic PD-L antibody in an IHCassay of a tumor tissue section or by flow cytometry. Alternatively,PD-L protein expression by tumor cells may be detected by PET imaging,using a binding agent (e.g., antibody fragment, affibody and the like)that specifically binds to the desired PD-L target, e.g., PD-L1 orPD-L2. Techniques for detecting and measuring PD-L mRNA expressioninclude RT-PCR and realtime quantitative RT-PCR.

Several approaches have been described for quantifying PD-L1 proteinexpression in IHC assays of tumor tissue sections. See, e.g., Thompson.R. H., et al., PNAS 101 (49); 17174-17179 (2004); Thompson, R. H. etal., Cancer Res. 66:3381-3385 (2006); Gadiot, J., et al., Cancer117:2192-2201 (2011); Taube, J. M. et al., Sci Transl Med 4, 127ra37(2012); and Toplian, S. L. et al., New Eng. J Med. 366 (26): 2443-2454(2012).

One approach employs a simple binary end-point of positive or negativefor PD-L1 expression, with a positive result defined in terms of thepercentage of tumor cells that exhibit histologic evidence ofcell-surface membrane staining. A tumor tissue section is counted aspositive for PD-L1 expression is at least 1%, and preferably 5% of totaltumor cells.

In another approach, PD-L1 expression in the tumor tissue section isquantified in the tumor cells as well as in infiltrating immune cells,which predominantly comprise lymphocytes. The percentage of tumor cellsand infiltrating immune cells that exhibit membrane staining areseparately quantified as <5%, 5 to 9%, and then in 10% increments up to100%. For tumor cells, PD-L1 expression is counted as negative if thescore is <5% score and positive if the score is ≧5%. PD-L1 expression inthe immune infiltrate is reported as a semi-quantitative measurementcalled the adjusted inflammation score (AIS), which is determined bymultiplying the percent of membrane staining cells by the intensity ofthe infiltrate, which is graded as none (0), mild (score of 1, rarelymphocytes), moderate (score of 2, focal infiltration of tumor bylymphohistiocytic aggregates), or severe (score of 3, diffuseinfiltration). A tumor tissue section is counted as positive for PD-L1expression by immune infiltrates if the AIS is ≧5.

The level of PD-L mRNA expression may be compared to the mRNA expressionlevels of one or more reference genes that are frequently used inquantitative RT-PCR, such as ubiquitin C.

In some embodiments, a level of PD-L1 expression (protein and/or mRNA)by malignant cells and/or by infiltrating immune cells within a tumor isdetermined to be “overexpressed” or “elevated” based on comparison withthe level of PD-L1 expression (protein and/or mRNA) by an appropriatecontrol. For example, a control PD-L protein or mRNA expression levelmay be the level quantified in nonmalignant cells of the same type or ina section from a matched normal tissue. In some preferred embodiments,PD-L1 expression in a tumor sample is determined to be elevated if PD-L1protein (and/or PD-L1 mRNA) in the sample is at least 10%, 20%, or 30%greater than in the control.

“RECIST 1.1 Response Criteria” as used herein means the definitions setforth in Eisenhauer et al., E. A. et al., Eur. J Cancer 45:228-247(2009) for target lesions or nontarget lesions, as appropriate based onthe context in which response is being measured.

“Sustained response” means a sustained therapeutic effect aftercessation of treatment with a therapeutic agent, or a combinationtherapy described herein. In some embodiments, the sustained responsehas a duration that is at least the same as the treatment duration, orat least 1.5, 2.0, 2.5 or 3 times longer than the treatment duration.

“Tissue Section” refers to a single part or piece of a tissue sample,e.g., a thin slice of tissue cut from a sample of a normal tissue or ofa tumor.

“Treat” or “treating” a cancer as used herein means to administer acombination therapy of a PD-1 antagonist and a VEGFR inhibitor to asubject having a cancer, or diagnosed with a cancer, to achieve at leastone positive therapeutic effect, such as for example, reduced number ofcancer cells, reduced tumor size, reduced rate of cancer cellinfiltration into peripheral organs, or reduced rate of tumor metastasisor tumor growth. Positive therapeutic effects in cancer can be measuredin a number of ways (See, W. A. Weber, J. Nucl. Med. 50:1S-10S (2009)).For example, with respect to tumor growth inhibition, according to NCIstandards, a T/C ≦42% is the minimum level of anti-tumor activity. AT/C<10% is considered a high anti-tumor activity level, with T/C(%)=Median tumor volume of the treated/Median tumor volume of thecontrol×100. In some embodiments, the treatment achieved by acombination of the invention is any of PR, CR, OR, PFS, DFS and OS. PFS,also referred to as “Time to Tumor Progression” indicates the length oftime during and after treatment that the cancer does not grow, andincludes the amount of time patients have experienced a CR or PR, aswell as the amount of time patients have experienced SD. DFS refers tothe length of time during and after treatment that the patient remainsfree of disease. OS refers to a prolongation in life expectancy ascompared to naive or untreated individuals or patients. In somepreferred embodiments, response to a combination of the invention is anyof PR, CR, PFS, DFS, OR or OS that is assessed using RECIST 1.1 responsecriteria. The treatment regimen for a combination of the invention thatis effective to treat a cancer patient may vary according to factorssuch as the disease state, age, and weight of the patient, and theability of the therapy to elicit an anti-cancer response in the subject.While an embodiment of any of the aspects of the invention may not beeffective in achieving a positive therapeutic effect in every subject,it should do so in a statistically significant number of subjects asdetermined by any statistical test known in the art such as theStudent's t-test, the chi²-test, the U-test according to Mann andWhitney, the Kruskal-Wallis test (H-test), Jonckheere-Terpstra-test andthe Wilcoxon-test.

The terms “treatment regimen”, “dosing protocol” and “dosing regimen”are used interchangeably to refer to the dose and timing ofadministration of each therapeutic agent in a combination of theinvention.

“Tumor” as it applies to a subject diagnosed with, or suspected ofhaving, a cancer refers to a malignant or potentially malignant neoplasmor tissue mass of any size, and includes primary tumors and secondaryneoplasms. A solid tumor is an abnormal growth or mass of tissue thatusually does not contain cysts or liquid areas. Different types of solidtumors are named for the type of cells that form them. Examples of solidtumors are sarcomas, carcinomas, and lymphomas. Leukemias (cancers ofthe blood) generally do not form solid tumors (National CancerInstitute, Dictionary of Cancer Terms).

“Tumor burden” also referred to as “tumor load”, refers to the totalamount of tumor material distributed throughout the body. Tumor burdenrefers to the total number of cancer cells or the total size oftumor(s), throughout the body, including lymph nodes and bone narrow.Tumor burden can be determined by a variety of methods known in the art,such as, e.g. by measuring the dimensions of tumor(s) upon removal fromthe subject, e.g., using calipers, or while in the body using imagingtechniques, e.g., ultrasound, bone scan, computed tomography (CT) ormagnetic resonance imaging (MRI) scans.

The term “tumor size” refers to the total size of the tumor which can bemeasured as the length and width of a tumor. Tumor size may bedetermined by a variety of methods known in the art, such as, e.g. bymeasuring the dimensions of tumor(s) upon removal from the subject,e.g., using calipers, or while in the body using imaging techniques,e.g., bone scan, ultrasound, CT or MRI scans.

“Variable regions” or “V region” as used herein means the segment of IgGchains which is variable in sequence between different antibodies. Itextends to Kabat residue 109 in the light chain and 113 in the heavychain.

“VEGFR inhibitor” means a small molecule inhibitor of vascularendothelial growth factor (VEGF) receptor or a monoclonal antibodyagainst vascular endothelial growth factor (VEGF). In an embodiment, a“VEGFR inhibitor” means a small molecule inhibitor of vascularendothelial growth factor (VEGF) receptor. Specific VEGFR inhibitorsuseful as the VEGFR inhibitor in the treatment method, medicaments anduses of the present invention, include axitinib, sunitinib, sorafenib,tivozanib, and bevacizumab. In an embodiment, specific VEGFR inhibitorsuseful as the VEGFR inhibitor in the treatment method, medicaments anduses of the present invention, include axitinib, sunitinib, sorafenib,and tivozanib.

In an embodiment of the treatment method, medicaments and uses of thepresent invention, the VEGFR inhibitor is the compound,N-methyl-2-[3-((E)-2-pyridin-2-yl-vinyl)-1H-indazol-6-ylsulfanyl]-benzamideor6-[2-(methylcarbamoyl)phenylsulfanyl]-3-E-[2-(pyridin-2-yl)ethenyl]indazole,of the following structure:

which is known as axitinib or AG-013736.

Axitinib is a potent and selective inhibitor of vascular endothelialgrowth factor (VEGF) receptors 1, 2 and 3. These receptors areimplicated in pathologic angiogenesis, tumor growth, and metastaticprogression of cancer. Axitinib has been shown to potently inhibitVEGF-mediated endothelial cell proliferation and survival (Hu-Lowe, D.D., et al., Clin Cancer Res 14: 7272-7283 (2008); Solowiej, S., et al.,Biochemistry 48: 7019-31 (2009)). Clinical trials are currently on-goingor have been conducted to study the use of axitinib for the treatment ofvarious cancers, including liver cancer, melanoma, mesothelioma,non-small cell lung cancer, prostate cancer, renal cell carcinoma, softtissue sarcomas and solid tumors. Inlyta® (axitinib) has been approvedin the United States, Europe, Japan and other jurisdictions for thetreatment of renal cell carcinoma.

Axitinib, as well as pharmaceutically acceptable salts thereof, isdescribed in U.S. Pat. No. 6,534,524. Methods of making axitinib aredescribed in U.S. Pat. Nos. 6,884,890 and 7,232,910, in U.S. PublicationNos. 2006-0091067 and 2007-0203196 and in International Publication No.WO 2006/048745. Dosage forms of axitinib are described in U.S.Publication No. 2004-0224988. Polymorphic forms and pharmaceuticalcompositions of axitinib are also described in U.S. Pat. No. 8,791,140and U.S. Publication Nos. 2006-0094763, 2008-0274192, and 2014-0248347.Uses of axitinib, including use as a single agent or in combinationtreatment, are described in U.S. Pat. No. 7,141,581 and in U.S.Publication No. 2014-0288125. The patents and patent applications listedabove are incorporated herein by reference.

Axitinib is understood to include reference to salts thereof, unlessotherwise indicated. Axitinib is basic in nature and capable of forminga wide variety of salts with various inorganic and organic acids. Theterm “salt(s)”, as employed herein, denotes acidic salts formed withinorganic and/or organic acids. Pharmaceutically acceptable salts ofaxitinib may be formed, for example, by reacting axitinib with an amountof acid, such as an equivalent amount, in a medium such as one in whichthe salt precipitates or in an aqueous medium followed bylyophilization.

Exemplary acid addition salts of axitinib include acetates, ascorbates,benzoates, benzenesulfonates, bisulfates, borates, butyrates, citrates,camphorates, camphorsulfonates, fumarates, hydrochlorides,hydrobromides, hydroiodides, lactates, maleates, methanesulfonates,naphthalenesulfonates, nitrates, oxalates, phosphates, propionates,salicylates, succinates, sulfates, tartarates, thiocyanates,toluenesulfonates (also known as tosylates,) and the like. Additionally,acids which are generally considered suitable for the formation ofpharmaceutically useful salts from basic pharmaceutical compounds arediscussed, for example, by S. Berge et al, Journal of PharmaceuticalSciences (1977) 66(1) 1-19; P. Gould, International J. of Pharmaceutics(1986) 33 201-217; Anderson et al, The Practice of Medicinal Chemistry(1996), Academic Press, New York; and in The Orange Book (Food & DrugAdministration, Washington, D.C. on their website). These disclosuresare incorporated herein by reference thereto.

All such acid salts are intended to be pharmaceutically acceptable saltswithin the scope of axitinib, as used in the present invention and allacid salts are considered equivalent to the free forms of thecorresponding compound for purposes of the invention.

Prodrugs of axitinib are also contemplated for use in the methods,medicaments and uses of the present invention. The term “prodrug”, asemployed herein, denotes a compound that is a drug precursor which, uponadministration to a subject, undergoes chemical conversion by metabolicor chemical processes to yield axitinib or a salt thereof. A discussionof prodrugs is provided in T. Higuchi and V. Stella, Pro-drugs as NovelDelivery Systems (1987) 14 of the A.C.S. Symposium Series, and inBioreversible Carriers in Drug Design, (1987) Edward B. Roche, ed.,American Pharmaceutical Association and Pergamon Press, both of whichare incorporated herein by reference thereto.

II. METHODS, USES AND MEDICAMENTS

In one aspect of the invention, the invention provides a method fortreating a cancer in an individual comprising administering to theindividual a combination therapy which comprises a PD-1 antagonist and aVEGR inhibitor.

The combination therapy may also comprise one or more additionaltherapeutic agents. The additional therapeutic agent may be, e.g., achemotherapeutic other than a VEGR inhibitor, a biotherapeutic agent(including but not limited to antibodies to VEGF, EGFR, Her2/neu, othergrowth factor receptors, CD20, CD40, CD-40L, CTLA-4, OX-40, 4-1BB, andICOS), an immunogenic agent (for example, attenuated cancerous cells,tumor antigens, antigen presenting cells such as dendritic cells pulsedwith tumor derived antigen or nucleic acids, immune stimulatingcytokines (for example, IL-2, IFNα2, GM-CSF), and cells transfected withgenes encoding immune stimulating cytokines such as but not limited toGM-CSF).

Examples of chemotherapeutic agents include alkylating agents such asthiotepa and cyclosphosphamide; alkyl sulfonates such as busulfan,improsulfan and piposulfan; aziridines such as benzodopa, carboquone,meturedopa, and uredopa; ethylenimines and methylamelamines includingaltretamine, triethylenemelamine, trietylenephosphoramide,triethylenethiophosphoramide and trimethylolomelamine; acetogenins(especially bullatacin and bullatacinone); a camptothecin (including thesynthetic analogue topotecan); bryostatin; callystatin; CC-1065(including its adozelesin, carzelesin and bizelesin syntheticanalogues); cryptophycins (particularly cryptophycin 1 and cryptophycin8); dolastatin; duocarmycin (including the synthetic analogues, KW-2189and CBI-TMI); eleutherobin; pancratistatin; a sarcodictyin;spongistatin; nitrogen mustards such as chlorambucil, chlornaphazine,cholophosphamide, estramustine, ifosfamide, mechlorethamine,mechlorethamine oxide hydrochloride, melphalan, novembichin,phenesterine, prednimustine, trofosfamide, uracil mustard; nitrosureassuch as carmustine, chlorozotocin, fotemustine, lomustine, nimustine,ranimustine; antibiotics such as the enediyne antibiotics (e.g.calicheamicin, especially calicheamicin gamma1I and calicheamicin phiI1,see, e.g., Agnew, Chem. Intl. Ed. Engl., 33:183-186 (1994); dynemicin,including dynemicin A; bisphosphonates, such as clodronate; anesperamicin; as well as neocarzinostatin chromophore and relatedchromoprotein enediyne antibiotic chromomophores), aclacinomysins,actinomycin, authramycin, azaserine, bleomycins, cactinomycin,carabicin, caminomycin, carzinophilin, chromomycins, dactinomycin,daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, doxorubicin(including morpholino-doxorubicin, cyanomorpholino-doxorubicin,2-pyrrolino-doxorubicin and deoxydoxorubicin), epirubicin, esorubicin,idarubicin, marcellomycin, mitomycins such as mitomycin C, mycophenolicacid, nogalamycin, olivomycins, peplomycin, potfiromycin, puromycin,quelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin,ubenimex, zinostatin, zorubicin; anti-metabolites such as methotrexateand 5-fluorouracil (5-FU); folic acid analogues such as denopterin,methotrexate, pteropterin, trimetrexate; purine analogs such asfludarabine, 6-mercaptopurine, thiamiprine, thioguanine; pyrimidineanalogs such as ancitabine, azacitidine, 6-azauridine, carmofur,cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine;androgens such as calusterone, dromostanolone propionate, epitiostanol,mepitiostane, testolactone; anti-adrenals such as aminoglutethimide,mitotane, trilostane; folic acid replenisher such as frolinic acid;aceglatone; aldophosphamide glycoside; aminolevulinic acid; eniluracil;amsacrine; bestrabucil; bisantrene; edatraxate; defofamine; demecolcine;diaziquone; elformithine; elliptinium acetate; an epothilone; etoglucid;gallium nitrate; hydroxyurea; lentinan; lonidamine; maytansinoids suchas maytansine and ansamitocins; mitoguazone; mitoxantrone; mopidamol;nitracrine; pentostatin; phenamet; pirarubicin; losoxantrone;podophyllinic acid; 2-ethylhydrazide; procarbazine; razoxane; rhizoxin;sizofuran; spirogermanium; tenuazonic acid; triaziquone; 2,2′,2″-trichlorotriethylamine; trichothecenes (especially T-2 toxin,verracurin A, roridin A and anguidine); urethan; vindesine; dacarbazine;mannomustine; mitobronitol; mitolactol; pipobroman; gacytosine;arabinoside (“Ara-C”); cyclophosphamide; thiotepa; taxoids, e.g.paclitaxel and doxetaxel; chlorambucil; gemcitabine; 6-thioguanine;mercaptopurine; methotrexate; platinum analogs such as cisplatin andcarboplatin; vinblastinc; platinum; etoposide (VP-16); ifosfamide;mitoxantrone; vincristine; vinorelbine; novantrone; teniposide;edatrexate; daunomycin; aminopterin; xeloda; ibandronate; CPT-11;topoisomerase inhibitor RFS 2000; difluoromethylornithine (DMFO);retinoids such as retinoic acid; capecitabine; and pharmaceuticallyacceptable salts, acids or derivatives of any of the above. Alsoincluded are anti-hormonal agents that act to regulate or inhibithormone action on tumors such as anti-estrogens and selective estrogenreceptor modulators (SERMs), including, for example, tamoxifen,raloxifene, droloxifene, 4-hydroxytamoxifen, trioxifene, keoxifene,LY117018, onapristone, and toremifene (Fareston); aromatase inhibitorsthat inhibit the enzyme aromatase, which regulates estrogen productionin the adrenal glands, such as, for example, 4(5)-imidazoles,aminoglutethimide, megestrol acetate, exemestane, formestane, fadrozole,vorozole, letrozole, and anastrozole; and anti-androgens such asflutamide, nilutamide, bicalutamide, leuprolide, and goserelin; andpharmaceutically acceptable salts, acids or derivatives of any of theabove.

Each therapeutic agent in a combination therapy of the invention may beadministered either alone or in a medicament (also referred to herein asa pharmaceutical composition) which comprises the therapeutic agent andone or more pharmaceutically acceptable carriers, excipients anddiluents, according to standard pharmaceutical practice.

Each therapeutic agent in a combination therapy of the invention may beadministered simultaneously (i.e., in the same medicament), concurrently(i.e., in separate medicaments administered one right after the other inany order) or sequentially in any order. Sequential administration isparticularly useful when the therapeutic agents in the combinationtherapy are in different dosage forms (one agent is a tablet or capsuleand another agent is a sterile liquid) and/or are administered ondifferent dosing schedules, e.g., a chemotherapeutic that isadministered at least daily and a biotherapeutic that is administeredless frequently, such as once weekly, once every two weeks, or onceevery three weeks.

In some embodiments, the VEGFR inhibitor is administered beforeadministration of the PD-1 antagonist, while in other embodiments, theVEGFR inhibitor is administered after administration of the PD-1antagonist.

In some embodiments, at least one of the therapeutic agents in thecombination therapy is administered using the same dosage regimen (dose,frequency and duration of treatment) that is typically employed when theagent is used as monotherapy for treating the same cancer. In otherembodiments, the patient receives a lower total amount of at least oneof the therapeutic agents in the combination therapy than when the agentis used as monotherapy, e.g., smaller doses, less frequent doses, and/orshorter treatment duration.

Each small molecule therapeutic agent in a combination therapy of theinvention can be administered orally or parenterally, including theintravenous, intramuscular, intraperitoneal, subcutaneous, rectal,topical, and transdermal routes of administration.

A combination therapy of the invention may be used prior to or followingsurgery to remove a tumor and may be used prior to, during or afterradiation therapy.

In some embodiments, a combination therapy of the invention isadministered to a patient who has not been previously treated with abiotherapeutic or chemotherapeutic agent, i.e., is treatment-naïve. Inother embodiments, the combination therapy is administered to a patientwho failed to achieve a sustained response after prior therapy with abiotherapeutic or chemotherapeutic agent, i.e., istreatment-experienced.

A combination therapy of the invention is typically used to treat atumor that is large enough to be found by palpation or by imagingtechniques well known in the art, such as MRI, ultrasound, or CAT scan.In some preferred embodiments, a combination therapy of the invention isused to treat an advanced stage tumor having dimensions of at leastabout 200 mm 300 mm³, 400 mm³, 500 mm³, 750 mm³, or up to 1000 mm³.

A combination therapy of the invention is preferably administered to ahuman patient who has a cancer that tests positive for PD-L1 expression.In some preferred embodiments, PD-L1 expression is detected using adiagnostic anti-human PD-L antibody, or antigen binding fragmentthereof, in an IHC assay on an FFPE or frozen tissue section of a tumorsample removed from the patient. Typically, the patient's physicianwould order a diagnostic test to determine PD-L1 expression in a tumortissue sample removed from the patient prior to initiation of treatmentwith the PD-1 antagonist and VEGFR inhibitor, but it is envisioned thatthe physician could order the first or subsequent diagnostic tests atany time after initiation of treatment, such as for example aftercompletion of a treatment cycle.

Selecting a dosage regimen (also referred to herein as an administrationregimen) for a combination therapy of the invention depends on severalfactors, including the serum or tissue turnover rate of the entity, thelevel of symptoms, the immunogenicity of the entity, and theaccessibility of the target cells, tissue or organ in the individualbeing treated. Preferably, a dosage regimen maximizes the amount of eachtherapeutic agent delivered to the patient consistent with an acceptablelevel of side effects. Accordingly, the dose amount and dosing frequencyof each biotherapeutic and chemotherapeutic agent in the combinationdepends in part on the particular therapeutic agent, the severity of thecancer being treated, and patient characteristics. Guidance in selectingappropriate doses of antibodies, cytokines, and small molecules areavailable. See, e.g., Wawrzynczak (1996) Antibody Therapy, BiosScientific Pub. Ltd, Oxfordshire, UK; Kresina (ed.) (1991) MonoclonalAntibodies, Cytokines and Arthritis. Marcel Dekker, New York, N.Y.; Bach(ed.) (1993) Monoclonal Antibodies and Peptide Therapy in AutoimmuneDiseases, Marcel Dekker, New York, N.Y.; Baert et al. (2003) New Engl.J. Med. 348:601-608; Milgrom et al. (1999) New Engl. J. Med.341:1966-1973; Slamon et al. (2001) New Engl. J. Med. 344:783-792;Beniaminovitz et al. (2000) New Engl. J. Med. 342:613-619; Ghosh et al.(2003) New Engl. J. Med. 348:24-32; Lipsky et al. (2000) New Engl. J.Med. 343:1594-1602; Physicians' Desk Reference 2003 (Physicians' DeskReference, 57th Ed); Medical Economics Company; ISBN: 1563634457; 57thedition (November 2002). Determination of the appropriate dosage regimenmay be made by the clinician, e.g., using parameters or factors known orsuspected in the art to affect treatment or predicted to affecttreatment, and will depend, for example, the patient's clinical history(e.g., previous therapy), the type and stage of the cancer to be treatedand biomarkers of response to one or more of the therapeutic agents inthe combination therapy.

Biotherapeutic agents in a combination therapy of the invention may beadministered by continuous infusion, or by doses at intervals of, e.g.,daily, every other day, three times per week, or one time each week, twoweeks, three weeks, monthly, bimonthly, etc. A total weekly dose isgenerally at least 0.05 μg/kg, 0.2 μg/kg, 0.5 μg/kg, 1 μg/kg, 10 μg/kg,100 μg/kg, 0.2 mg/kg, 1.0 mg/kg, 2.0 mg/kg, 10 mg/kg, 25 mg/kg, 50 mg/kgbody weight or more. See, e.g., Yang et al. (2003) New Engl. J. Med.349:427-434; Herold et al. (2002) New Engl. J. Med. 346:1692-1698; Liuet al. (1999) J. Neurol. Neurosurg. Psych. 67:451-456; Portielji et al.(20003) Cancer Immunol. Immunother. 52:133-144.

In some embodiments that employ an anti-human PD-1 mAb as the PD-1antagonist in the combination therapy, the dosing regimen will compriseadministering the anti-human PD-1 mAb at a dose of 1, 2, 3, 5 or 10mg/kg at intervals of about 14 days (±2 days) or about 21 days (±2 days)or about 30 days (±2 days) throughout the course of treatment.

In other embodiments that employ an anti-human PD-1 mAb as the PD-1antagonist in the combination therapy, the dosing regimen will compriseadministering the anti-human PD-1 mAb at a dose of from about 0.005mg/kg to about 10 mg/kg, with intra-patient dose escalation. In otherescalating dose embodiments, the interval between doses will beprogressively shortened, e.g., about 30 days (±2 days) between the firstand second dose, about 14 days (±2 days) between the second and thirddoses. In certain embodiments, the dosing interval will be about 14 days(±2 days), for doses subsequent to the second dose.

In certain embodiments, a subject will be administered an intravenous(IV) infusion of a medicament comprising any of the PD-1 antagonistsdescribed herein.

In one preferred embodiment of the invention, the PD-1 antagonist in thecombination therapy is nivolumab, which is administered intravenously ata dose selected from the group consisting of: 1 mg/kg Q2W, 2 mg/kg Q2W,3 mg/kg Q2W, 5 mg/kg Q2W, 10 mg Q2W, 1 mg/kg Q3W, 2 mg/kg Q3W, 3 mg/kgQ3W, 5 mg/kg Q3W, and 10 mg Q3W.

In another preferred embodiment of the invention, the PD-1 antagonist inthe combination therapy is MK-3475, which is administered in a liquidmedicament at a dose selected from the group consisting of 1 mg/kg Q2W,2 mg/kg Q2W, 3 mg/kg Q2W, 5 mg/kg Q2W, 10 mg Q2W, 1 mg/kg Q3W, 2 mg/kgQ3W, 3 mg/kg Q3W, 5 mg/kg Q3W, 10 mg Q3W and flat-dose equivalents ofany of these doses, i.e., such as 200 mg Q3W. In some particularlypreferred embodiments, MK-3475 is administered as a liquid medicamentwhich comprises 25 mg/ml MK-3475, 7% (w/v) sucrose, 0.02% (w/v)polysorbate 80 in 10 mM histidine buffer pH 5.5, and the selected doseof the medicament is administered by IV infusion over a time period ofabout 30 minutes.

The optimal dose for MK-3475 in combination with axitinib may beidentified by dose escalation of one or both of these agents. In oneembodiment, axitinib is administered at 5 mg BID and MK-3475 isadministered at a starting dose of 2 mg/kg Q2W, and if this dosecombination is tolerated by the patient, the MK-3475 dose is increasedup to a dose of 10 mg/kg Q2W, while if the starting dose combination isnot tolerated by the patient, then the dose of MK-3475 is reduced to 1mg/kg Q2W.

In another embodiment, axitinib is administered at 5 mg BID and MK-3475is administered at a starting dose of 2 mg/kg Q3W, and if this startingdose combination is not tolerated by the patient, then the dose ofMK-3475 is reduced to 1 mg/kg Q3W.

In another embodiment, axitinib is administered at 5 mg BID and MK-3475is administered at a starting dose of 2 mg/kg Q3W, and if this dosecombination is not tolerated by the patient, then the dose of axitinibis reduced to 3 mg BID.

In an embodiment, 5 mg of axitinib is administered with our without foodBID, with each dose administered about 12 hours apart. On the day ofMK-3475 administration, axitinib may be given prior to or after theMK-3475 administration.

In some embodiments, the patient is treated with a 7-day lead-in periodof single-agent axitinib directly preceding the administration of theMK-3475 and axitinib combination.

In some embodiments, a treatment cycle begins with the first day ofcombination treatment and last for 2 weeks. In such embodiments, thecombination therapy is preferably administered for at least 12 weeks (6cycles of treatment), more preferably at least 24 weeks, and even morepreferably at least 2 weeks after the patient achieves a CR.

In some preferred embodiments, the dose of axitinib is increased after 6cycles if the patient tolerates axitinib with no drug-related grade >2adverse events for 2 consecutive weeks. The axitinib dose may beincreased by 2 mg BID each cycle up to a maximum dose of 10 mg BID.

In some embodiments, the patient is selected for treatment with thecombination therapy of the invention is the patient has been diagnosedwith advanced RCC with predominantly clear cell subtype, and the primarytumor has been resected. Preferably, the patient has not received priorsystemic therapy for advanced RCC.

The present invention also provides a medicament which comprises a PD-1antagonist as described above and a pharmaceutically acceptableexcipient. When the PD-1 antagonist is a biotherapeutic agent, e.g., amAb, the antagonist may be produced in CHO cells using conventional cellculture and recovery/purification technologies.

In some embodiments, a medicament comprising an anti-PD-1 antibody asthe PD-1 antagonist may be provided as a liquid formulation or preparedby reconstituting a lyophilized powder with sterile water for injectionprior to use. WO 2012/135408 describes the preparation of liquid andlyophilized medicaments comprising MK-3475 that are suitable for use inthe present invention. In some preferred embodiments, a medicamentcomprising MK-3475 is provided in a glass vial which contains about 50mg of MK-3475.

The present invention also provides a medicament which comprisesaxitinib and a pharmaceutically acceptable excipient.

The anti-PD-1 and VEGFR inhibitor medicaments described herein may beprovided as a kit which comprises a first container and a secondcontainer and a package insert. The first container contains at leastone dose of a medicament comprising an anti-PD-1 antagonist, the secondcontainer contains at least one dose of a medicament comprising a VEGFRinhibitor, and the package insert, or label, which comprisesinstructions for treating a patient for cancer using the medicaments.The first and second containers may be comprised of the same ordifferent shape (e.g., vials, syringes and bottles) and/or material(e.g., plastic or glass). The kit may further comprise other materialsthat may be useful in administering the medicaments, such as diluents,filters, IV bags and lines, needles and syringes. In some preferredembodiments of the kit, the anti-PD-1 antagonist is an anti-PD-1antibody and the instructions state that the medicaments are intendedfor use in treating a patient having a cancer that tests positive forPD-L1 expression by an IHC assay.

These and other aspects of the invention, including the exemplaryspecific embodiments listed below, will be apparent from the teachingscontained herein.

Exemplary Specific Embodiments of the Invention

1. A method for treating a cancer in an individual comprisingadministering to the individual a combination therapy which comprises aPD-1 antagonist and a VEGFR inhibitor.2. The method of embodiment 1, wherein the PD-1 antagonist is amonoclonal antibody, or an antigen binding fragment thereof.3. The method of embodiment 1 or 2, wherein the VEGFR inhibitor thecompoundN-methyl-2-[3-((E)-2-pyridin-2-yl-vinyl)-1H-indazol-6-ylsulfanyl]-benzamideor a pharmaceutically acceptable salt thereof.4. A medicament comprising a PD-1 antagonist for use in combination witha VEGFR inhibitor for treating a cancer in an individual, wherein thePD-1 antagonist is a monoclonal antibody, or an antigen binding fragmentthereof.5. A medicament comprising a VEGFR inhibitor for use in combination witha PD-1 antagonist for treating a cancer in an individual.6. The medicament of embodiment 4 or 5, which further comprises apharmaceutically acceptable excipient.7. Use of a PD-1 antagonist in the manufacture of medicament fortreating a cancer in an individual when administered in combination witha VEGFR inhibitor.6. Use of a VEGFR inhibitor compound in the manufacture of a medicamentfor treating a cancer in an individual when administered in combinationwith a PD-1 antagonist.7. Use of a PD-1 antagonist and a VEGFR inhibitor in the manufacture ofmedicaments for treating a cancer in an individual.8. A kit which comprises a first container, a second container and apackage insert, wherein the first container comprises at least one doseof a medicament comprising an anti-PD-1 antagonist, the second containercomprises at least one dose of a medicament comprising a VEGFRinhibitor, and the package insert comprises instructions for treating anindividual for cancer using the medicaments.9. The kit of embodiment 8, wherein the instructions state that themedicaments are intended for use in treating an individual having acancer that tests positive for PD-L1 expression by animmunohistochemical (IHC) assay.10. The method, medicament, use or kit of any of embodiments 1 to 9,wherein the individual is a human and the PD-1 antagonist is amonoclonal antibody, or an antigen binding fragment thereof, whichspecifically binds to human PD-L1 and blocks the binding of human PD-Lto human PD-1.11. The method, medicament, use or kit of embodiment 9, wherein the PD-1antagonist is MPDL3280A. BMS-936559, MEDI4736, MSB0010718C or amonoclonal antibody which comprises the heavy chain and light chainvariable regions of SEQ ID NO:24 and SEQ ID NO:21, respectively, ofWO2013/019906.12. The method, medicament, use or kit of any of embodiments 1 to 9,wherein the individual is a human, and the PD-1 antagonist is amonoclonal antibody, or an antigen binding fragment thereof, whichspecifically binds to human PD-1 and blocks the binding of human PD-L tohuman PD-1.13. The method, medicament, use or kit of embodiment 12, wherein thePD-1 antagonist also blocks binding of human PD-L2 to human PD-1.14. The method, medicament, use or kit of embodiment 13, wherein themonoclonal antibody, or antigen binding fragment thereof, comprises: (a)light chain CDRs of SEQ ID NOs: 1, 2 and 3 and heavy chain CDRs of SEQID NOs: 4, 5 and 6; or (b) light chain CDRs of SEQ ID NOs: 7, 8 and 9and heavy chain CDRs of SEQ ID NOs: 10, 11 and 12.15. The method, medicament, use or kit of embodiment 13, wherein themonoclonal antibody, or antigen binding fragment thereof, compriseslight chain CDRs of SEQ ID NOs: 7, 8 and 9 and heavy chain CDRs of SEQID NOs: 10, 11 and 12.16. The method, medicament, use or kit of embodiment 13, wherein thePD-1 antagonist is an anti-PD-1 monoclonal antibody which comprises aheavy chain and a light chain, and wherein the heavy chain comprises SEQID NO:21 and the light chain comprises SEQ ID NO:22.17. The method, medicament, use or kit of embodiment 13, wherein thePD-1 antagonist is an anti-PD-1 monoclonal antibody which comprises aheavy chain and a light chain, and wherein the heavy chain comprises SEQID NO:23 and the light chain comprises SEQ ID NO:24.18. The method, medicament, use or kit of any of embodiments 10-17,wherein the cancer is a solid tumor.19. The method, medicament, use or kit of any of embodiments 10-17,wherein the cancer is bladder cancer, breast cancer, clear cell kidneycancer, head/neck squamous cell carcinoma, lung squamous cell carcinoma,malignant melanoma, non-small-cell lung cancer (NSCLC), ovarian cancer,pancreatic cancer, prostate cancer, renal cell cancer, small-cell lungcancer (SCLC) or triple negative breast cancer.20. The method, medicament, use or kit of any of embodiments 10-17,wherein the cancer is advanced renal cell carcinoma.21. The method, medicament, use or kit of any of embodiments 10-17,wherein the individual has not been previously treated for advancedrenal cell carcinoma.22. The method, medicament, use or kit of any of embodiments 10-17,wherein the cancer is clear cell kidney cancer.23. The method, medicament, use or kit of any of embodiments 10-17,wherein the cancer is acute lymphoblastic leukemia (ALL), acute myeloidleukemia (AML), chronic lymphocytic leukemia (CLL), chronic myeloidleukemia (CML), diffuse large B-cell lymphoma (DLBCL), follicularlymphoma, Hodgkin's lymphoma (HL), mantle cell lymphoma (MCL), multiplemyeloma (MM), myeloid cell leukemia-1 protein (Mcl-1), myelodysplasticsyndrome (MDS), non-Hodgkin's lymphoma (NHL), or small lymphocyticlymphoma (SLL).24. The method, medicament, use or kit of any of embodiments 10-23, thecancer tests positive for human PD-L1.25. The method, medicament, use or kit of embodiment 24, wherein thehuman PD-L1 expression is elevated.26. The method, medicament, use or kit of embodiment 13, wherein thePD-1 antagonist is MK-3475 or nivolumab.27. The method, medicament, use or kit of embodiment 26, wherein theMK-3475 is formulated as a liquid medicament which comprises 25 mg/mlMK-3475, 7% (w/v) sucrose, 0.02% (w/v) polysorbate 80 in 10 mM histidinebuffer pH 5.5.28. The method, medicament, use or kit of any of embodiments 1 to 27,wherein the VEGR inhibitor is sunitinib, sorafenib or tivozanib.29. The method, medicament, use or kit of any of embodiments 1 to 27,wherein the VEGR inhibitor isN-methyl-2-[3-((E)-2-pyridin-2-yl-vinyl)-1H-indazol-6-ylsulfanyl]-benzamideor a pharmaceutically acceptable salt thereof.30. The method, medicament, use or kit of any of embodiments 1 to 27,wherein the VEFR inhibitor is axitinib and is formulated as a 1 mgtablet or a 5 mg tablet.31. A method for treating a human individual diagnosed with a cancer,comprising administering to the individual a combination therapy whichcomprises MK-3475 and axitinib, wherein (a) axitinib is administered ata dose of 5 mg BID and MK-3475 is administered at a dose selected fromthe group consisting of 1 mg/kg Q3W, 2 mg/kg Q3W and 200 mg Q3W or (b)axitinib is administered at a dose of 3 mg BID and MK-3475 isadministered at a dose selected from the group consisting of 1 mg/kgQ3W, 2 mg/kg Q3W and 200 mg Q3W.32. A medicament comprising MK-3475 for use in combination with axitinibfor treating a cancer in a human individual by a method comprisingadministering to the individual (a) axitinib at a dose of 5 mg BID andMK-3475 at a dose selected from the group consisting of 1 mg/kg Q3W, 2mg/kg Q3W and 200 mg/kg Q3W or (b) axitinib at a dose of 3 mg BID andMK-3475 at a dose selected from the group consisting of 1 mg/kg Q3W, 2mg/kg Q3W and 200 mg Q3W.33. A medicament comprising axitinib for use in combination with MK-3475for treating a cancer in a human individual by a method comprisingadministering to the individual (a) axitinib at a dose of 5 mg BID andMK-3475 at a dose selected from the group consisting of 1 mg/kg Q3W, 2mg/kg Q3W and 200 mg Q3W or (b) axitinib at a dose of 3 mg BID andMK-3475 at a dose selected from the group consisting of 1 mg/kg Q3W, 2mg/kg Q3W and 200 mg Q3W.34. The method or medicament of any of embodiments 31 to 33, whereinaxitinib is administered at a dose of 5 mg BID and MK-3475 isadministered at 1 mg/kg Q3W.35. The method or medicament of any of embodiments 31 to 33, whereinaxitinib is administered at a dose of 5 mg BID and MK-3475 isadministered at 2 mg/kg Q3W.36. The method or medicament of any of embodiments 31 to 33, whereinaxitinib is administered at a dose of 3 mg BID and MK-3475 isadministered at 1 mg/kg Q3W.37. The method or medicament of any of embodiments 31 to 33, whereinaxitinib is administered at a dose of 3 mg BID and MK-3475 isadministered at 2 mg/kg Q3W.38. The method or medicament of any of embodiments 31 to 33, whereinaxitinib is administered at a dose of 3 mg BID and MK-3475 isadministered at 200 mg Q3W.39. The method or medicament of any of embodiments 31 to 38, wherein thecancer is renal cell cancer.40. The method or medicament of embodiment 39, wherein the individualhas not been previously treated for renal cell cancer.41. The method or medicament of any of embodiments 31 to 38, wherein thecancer is clear cell kidney cancer.42. The method or medicament of any of embodiments 31 to 41, wherein atissue section of the cancer removed from the individual prior toadministration of the combination therapy tested positive for PD-L1expression.43. The method or medicament of embodiment 42, wherein at least 50% ofthe tumor cells in the tissue section tested positive for PD-L1expression by an immunohistochemical (IHC) assay.44. The method or medicament of embodiment 43, wherein the IHC assayemployed the antibody 22C3 to detect PD-L1 expression.45. The method or medicament of any of embodiments 31 to 44, whereinMK-3475 is administered by IV infusion.

General Methods

Standard methods in molecular biology are described Sambrook, Fritschand Maniatis (1982 & 1989 2^(nd) Edition, 2001 3^(rd) Edition) MolecularCloning, A Laboratory Manual, Cold Spring Harbor Laboratory Press, ColdSpring Harbor, N.Y.; Sambrook and Russell (2001) Molecular Cloning,3^(rd) ed., Cold Spring Harbor Laboratory Press, Cold Spring Harbor,N.Y.; Wu (1993) Recombinant DNA, Vol. 217, Academic Press, San Diego,Calif.). Standard methods also appear in Ausbel, et al. (2001) CurrentProtocols in Molecular Biology. Vols. 1-4, John Wiley and Sons, Inc. NewYork, N.Y., which describes cloning in bacterial cells and DNAmutagenesis (Vol. 1), cloning in mammalian cells and yeast (Vol. 2),glycoconjugates and protein expression (Vol. 3), and bioinformatics(Vol. 4).

Methods for protein purification including immunoprecipitation,chromatography, electrophoresis, centrifugation, and crystallization aredescribed (Coligan, et al. (2000) Current Protocols in Protein Science,Vol. 1, John Wiley and Sons, Inc., New York). Chemical analysis,chemical modification, post-translational modification, production offusion proteins, glycosylation of proteins are described (see, e.g.,Coligan, et al. (2000) Current Protocols in Protein Science, Vol. 2,John Wiley and Sons, Inc., New York; Ausubel, et al. (2001) CurrentProtocols in Molecular Biology, Vol. 3, John Wiley and Sons, Inc., NY,N.Y., pp. 16.0.5-16.22.17; Sigma-Aldrich, Co. (2001) Products for LifeScience Research, St. Louis, Mo.; pp. 45-89; Amersham Pharmacia Biotech(2001) BioDirectory, Piscataway, N.J., pp. 384-391). Production,purification, and fragmentation of polyclonal and monoclonal antibodiesare described (Coligan, et al. (2001) Current Protocols in Immunology,Vol. 1, John Wiley and Sons, Inc., New York; Harlow and Lane (1999)Using Antibodies, Cold Spring Harbor Laboratory Press, Cold SpringHarbor, N.Y.; Harlow and Lane, supra). Standard techniques forcharacterizing ligand/receptor interactions are available (see, e.g.,Coligan, et al. (2001) Current Protocols in Immunology, Vol. 4, JohnWiley. Inc., New York).

Monoclonal, polyclonal, and humanized antibodies can be prepared (see,e.g., Sheperd and Dean (eds.) (2000) Monoclonal Antibodies, Oxford Univ.Press, New York, N.Y.; Kontermann and Dubel (eds.) (2001) AntibodyEngineering, Springer-Verlag, New York; Harlow and Lane (1988)Antibodies A Laboratory Manual, Cold Spring Harbor Laboratory Press,Cold Spring Harbor, N.Y., pp. 139-243; Carpenter, et al. (2000) J.Immunol. 165:6205; He, et al. (1998) J. Immunol. 160:1029; Tang et al.(1999) J. Biol. Chem. 274:27371-27378; Baca et al. (1997). J. Biol.Chem. 272:10678-10684; Chothia et al. (1989) Nature 342:877-883; Footeand Winter (1992) J. Mol. Biol. 224:487-499; U.S. Pat. No. 6,329,511).

An alternative to humanization is to use human antibody librariesdisplayed on phage or human antibody libraries in transgenic mice(Vaughan et al. (1996) Nature Biotechnol. 14:309-314; Barbas (1995)Nature Medicine 1:837-839; Mendez et al. (1997) Nature Genetics15:146-156; Hoogenboom and Chames (2000) Immunol. Today 21:371-377;Barbas et al. (2001) Phage Display: A Laboratory Manual, Cold SpringHarbor Laboratory Press, Cold Spring Harbor, N.Y.; Kay et al. (1996)Phage Display of Peptides and Proteins: A Laboratory Manual, AcademicPress, San Diego, Calif.; de Bruin et al. (1999) Nature Biotechnol.17:397-399).

Purification of antigen is not necessary for the generation ofantibodies. Animals can be immunized with cells bearing the antigen ofinterest. Splenocytes can then be isolated from the immunized animals,and the splenocytes can fused with a myeloma cell line to produce ahybridoma (see, e.g., Meyaard et al. (1997) Immunity 7:283-290; Wrightet al. (2000) Immunity 13:233-242; Preston et al., supra; Kaithamana etal. (1999) J. Immunol. 163:5157-5164).

Antibodies can be conjugated, e.g., to small drug molecules, enzymes,liposomes, polyethylene glycol (PEG). Antibodies are useful fortherapeutic, diagnostic, kit or other purposes, and include antibodiescoupled, e.g., to dyes, radioisotopes, enzymes, or metals, e.g.,colloidal gold (see, e.g., Le Doussal et al. (1991) J. Immunol.146:169-175; Gibellini et al. (1998) J. Immunol. 160:3891-3898; Hsingand Bishop (1999) J. Immunol. 162:2804-2811; Everts et al. (2002) J.Immunol. 168:883-889).

Methods for flow cytometry, including fluorescence activated cellsorting (FACS), are available (see, e.g., Owens, et al. (1994) FlowCytometry Principles for Clinical Laboratory Practice, John Wiley andSons, Hoboken, N.J.; Givan (2001) Flow Cytometry, 2^(nd) ed.;Wiley-Liss, Hoboken, N.J.; Shapiro (2003) Practical Flow Cytometry, JohnWiley and Sons, Hoboken, N.J.). Fluorescent reagents suitable formodifying nucleic acids, including nucleic acid primers and probes,polypeptides, and antibodies, for use, e.g., as diagnostic reagents, areavailable (Molecular Probesy (2003) Catalogue, Molecular Probes, Inc.,Eugene, Oreg.; Sigma-Aldrich (2003) Catalogue, St. Louis, Mo.).

Standard methods of histology of the immune system are described (see,e.g., Muller-Harmelink (ed.) (1986) Human Thymus: Histopathologv andPathology, Springer Verlag, New York, N.Y.; Hiatt, et al. (2000) ColorAtlas of Histology, Lippincott, Williams, and Wilkins, Phila, Pa.;Louis, et al. (2002) Basic Histology: Text and Atlas, McGraw-Hill, NewYork, N.Y.).

Software packages and databases for determining, e.g., antigenicfragments, leader sequences, protein folding, functional domains,glycosylation sites, and sequence alignments, are available (see, e.g.,GenBank, Vector NTI® Suite (Informax, Inc, Bethesda, Md.); GCG WisconsinPackage (Accelrys, Inc., San Diego, Calif.); DeCypher® (TimeLogic Corp.,Crystal Bay, Nev.); Menne, et al. (2000) Bioinformatics 16: 741-742;Menne, et al. (2000) Bioinformatics Applications Note 16:741-742; Wren,et al. (2002) Comput. Methods Programs Biomed. 68:177-181; von Heijne(1983) Eur. J. Biochem. 133:17-21; von Heijne (1986) Nucleic Acids Res.14:4683-4690).

Example 1: Treatment of Patients with Renal Cell Carcinoma with aCombination of Axitinib and MK-3475

This study will evaluate the efficacy of a combination of axitinib andMK-3475 in human patients with RCC. Patients will be treated withaxitinib at 5 mg or 3 mg BID and with MK-3475 at 1 mg/kg or 2 mg/kgevery three weeks by intravenous infusion for a period of 18 months.

Dose Level MK-3475 Axitinib 1 (Starting Dose Level) 2 mg/kg IV q3wk 5 mgBID 1a 1 mg/kg IV q3wk 5 mg BID 1b 2 mg/kg IV q3wk 3 mg BID BID: twicedaily; q3wk: every 3 weeks.

It is expected that the combination of axitinib and MK-3475 will be moreefficacious than either treatment alone according to at least one of thefollowing outcome measures:

Duration of Response (DR) [Time Frame: 18 months]—Time in weeks from thefirst documentation of objective tumor response to objective tumorprogression or death due to any cancer. Duration of tumor response willbe calculated as (the date of the first documentation of objective tumorprogression or death due to cancer minus the date of the first CR or PRthat will be subsequently confirmed plus 1) divided by 7. DR will becalculated for the subgroup of participants with a confirmed objectivetumor response.

Percentage of Participants With Objective Response [Time Frame: 18months]-Percentage of participants with OR based assessment of confirmedcomplete remission (CR) or confirmed partial remission (PR) according toResponse Evaluation Criteria in Solid Tumors (RECIST). Confirmedremission are those with repeat bone marrow showing less than 5 percent(%) myeloblasts with normal maturation of all cell lines and absolutevalues of the peripheral blood lasting at least 2 months. PR are thosewith all CR criteria except at least 50% decrease in the blasts over thepretreatment.

Progression-Free Survival (PFS) [Time Frame: 18 months]—Median time fromthe first dose of study treatment to the first documentation ofobjective tumor progression or to death due to any cause, whicheveroccurs first. PFS calculated as (Weeks)=(first event date minus firstdose date plus 1) divided by 7.

Overall Survival (OS) [Time Frame: five years]—Overall survival will bethe duration from enrollment to death. For participants who are alive,overall survival will be censored at the last contact.

Eastern Cooperative Oncology Group [ECOG] performance status [TimeFrame: Up to 2.5 years]—ECOG-PS measured on-therapy (time between firstdose and last dose date with a 30-day lag) assessed participant'sperformance status on 5 point scale: 0=Fully active/able to carry on allpre-disease activities without restriction;

1=restricted in physically strenuous activity, ambulatory/able to carryout light or sedentary work; 2=ambulatory (>50% of waking hrs), capableof all self care, unable to carry out any work activities; 3=capable ofonly limited self care, confined to bed/chair >50% of waking hrs;4=completely disabled, cannot carry on any self care, totally confinedto bed/chair; 5=dead.

Presence (rate) or absence of blood biomarkers [Time Frame: Up to 2.5years]—To identify biomarkers (FGF, IL8, VEGF . . . ) of completeresponse and relapse/progression if occurs.

Patient eligibility for the study will be determined according to thefollowing criteria:

Ages Eligible for Study: 18 Years and older.

Genders Eligible for Study: Both. Accepts Healthy Volunteers: No.

Histologically or cytologically confirmed advanced RCC withpredominantly clear-cell subtype with primary tumor resected;at least one measurable lesion as defined by Response EvaluationCriteria In Solid Tumors (RECIST) version 1.1;Eastern Cooperative Oncology Group performance status 0 or 1; andcontrolled hypertension.

SEQ ID NO: Description 1 hPD-1.08A light chain CDR1 2 hPD-1.08A lightchain CDR2 3 hPD-1-08A light chain CDR3 4 hPD-1.08A heavy chain CDR1 5hPD-1.08A heavy chain CDR2 6 hPD-1.08A heavy chain CDR3 7 hPD-1.09Alight chain CDR1 8 hPD-1.09A light chain CDR2 9 hPD-1.09A light chainCDR3 10 hPD-1.09A heavy chain CDR1 11 hPD-1.09A heavy chain CDR2 12hPD-1.09A heavy chain CDR3 13 109A-H heavy chain variable region 14409A-H heavy chain full length 15 K09A-L-11 light chain variable region16 K09A-L-16 light chain variable region 17 K09A-L-17 light chainvariable region 18 K09A-L-11 light chain full length 19 K09A-L-16 lightchain full length 20 K09A-L-17 light chain full length 21 MK-3475 Heavychain 22 MK-3475 Light chain 23 Nivolumab Heavy chain 24 Nivolumab lightchain 25 Human PD-L1

REFERENCES

-   1. Sharpe, A. H, Wherry, E. J., Ahmed R., and Freeman G. J. The    function of programmed cell death 1 and its ligands in regulating    autoimmunity and infection. Nature Immunology (2007); 8:239-245.-   2. Dong H et al. Tumor-associated B7-H1 promotes T-cell apoptosis: a    potential mechanism of immune evasion. Nat Med. 2002 August;    8(8):793-800.-   3. Yang et al. PD-1 interaction contributes to the functional    suppression of T-cell responses to human uveal melanoma cells in    vitro. Invest Ophthalmol Vis Sci. 2008 June; 49(6 (2008): 49:    2518-2525.-   4. Ghebeh et al. The B7-H1 (PD-L1) T lymphocyte-inhibitory molecule    is expressed in breast cancer patients with infiltrating ductal    carcinoma: correlation with important high-risk propgnostic factors.    Neoplasia (2006) 8: 190-198.-   5. Hamanishi J et al. Programmed cell death 1 ligand 1 and    tumor-infiltrating CD8+ T lymphocytes are prognostic factors of    human ovarian cancer. Proceeding of the National Academy of Sciences    (2007): 104: 3360-3365.-   6. Thompson R H et al. Significance of B7-H1 overexpression in    kidney cancer. Clinical genitourin Cancer (2006): 5: 206-211.-   7. Nomi, T. Sho, M., Akahori, T., et al. Clinical significance and    therapeutic potential of the programmed death-1 ligand/programmed    death-1 pathway in human pancreatic cancer. Clinical Cancer Research    (2007); 13:2151-2157.-   8. Ohigashi Y et al. Clinical significance of programmed death-1    ligand-1 and programmed death-1 ligand 2 expression in human    esophageal cancer. Clin. Cancer Research (2005): 11: 2947-2953.-   9. Inman et al. PD-L1 (B7-H1) expression by urothelial carcinoma of    the bladder and BCG-induced granulomata: associations with localized    stage progression. Cancer (2007): 109: 1499-1505.-   10. Shimauchi T et al. Augmented expression of programmed death-1 in    both neoplasmatic and nonneoplastic CD4+ T-cells in adult T-cell    Leukemia/Lymphoma. Int. J. Cancer (2007): 121:2585-2590.-   11. Gao et al. Overexpression of PD-L1 significantly associates with    tumor aggressiveness and postoperative recurrence in human    hepatocellular carcinoma. Clinical Cancer Research (2009) 15:    971-979.-   12. Nakanishi J. Overexpression of B7-H1 (PD-L1) significantly    associates with tumor grade and postoperative prognosis in human    urothelial cancers. Cancer Immunol Immunother. (2007) 56: 1173-1182.-   13. Hino et al. Tumor cell expression of programmed cell death-1 is    a prognostic factor for malignant melanoma. Cancer (2010): 00: 1-9.-   14. Ghebeh H. Foxp3+ tregs and B7-H1+/PD-1+ T lymphocytes    co-infiltrate the tumor tissues of high-risk breast cancer patients:    implication for immunotherapy. BMC Cancer. 2008 Feb. 23; 8:57.-   15. Ahmadzadeh M et al. Tumor antigen-specific CD8 T cells    infiltrating the tumor express high levels of PD-1 and are    functionally impaired. Blood (2009) 114: 1537-1544.-   16. Thompson R H et al. PD-1 is expressed by tumor infiltrating    cells and is associated with poor outcome for patients with renal    carcinoma. Clinical Cancer Research (2007) 15: 1757-1761.

All references cited herein are incorporated by reference to the sameextent as if each individual publication, database entry (e.g. Genbanksequences or GeneID entries), patent application, or patent, wasspecifically and individually indicated to be incorporated by reference.This statement of incorporation by reference is intended by Applicants,pursuant to 37 C.F.R. §1.57(b)(1), to relate to each and everyindividual publication, database entry (e.g. Genbank sequences or GeneIDentries), patent application, or patent, each of which is clearlyidentified in compliance with 37 C.F.R. §1.57(b)(2), even if suchcitation is not immediately adjacent to a dedicated statement ofincorporation by reference. The inclusion of dedicated statements ofincorporation by reference, if any, within the specification does not inany way weaken this general statement of incorporation by reference.Citation of the references herein is not intended as an admission thatthe reference is pertinent prior art, nor does it constitute anyadmission as to the contents or date of these publications or documents.

1. A method for treating a cancer in an individual comprisingadministering to the individual a combination therapy which comprises anantagonist of a Programmed Death 1 protein (PD-1) and a VEGFR inhibitor,wherein the PD-1 antagonist is an anti-PD-1 monoclonal antibody whichcomprises a heavy chain and a light chain, wherein the heavy and lightchains comprise SEQ ID NO:21 and SEQ ID NO:22, respectively, and furtherwherein the VEGFR inhibitor isN-methyl-2-[3-((E)-2-pyridin-2-yl-vinyl)-1H-indazol-6-ylsulfanyl]-benzamideor a pharmaceutically acceptable salt thereof.
 2. The method of claim 1,wherein the individual is a human.
 3. The method of claim 1 or 2,wherein the cancer is a solid tumor.
 4. The method of claim 1 or 2,wherein the cancer is renal cell carcinoma.
 5. The method of any ofclaims 1 to 4, wherein the PD-1 antagonist is MK-3475 and the VEGFRinhibitor is axitinib.
 6. A medicament comprising an antagonist of aProgrammed Death 1 protein (PD-1) for use in combination with a VEGFRinhibitor for treating a cancer in an individual, wherein the PD-1antagonist is an anti-PD-1 monoclonal antibody which comprises a heavychain and a light chain, wherein the heavy and light chains comprise SEQID NO:21 and SEQ ID NO:22, respectively, and further wherein the VEGFRinhibitor isN-methyl-2-[3-((E)-2-pyridin-2-yl-vinyl)-1H-indazol-6-ylsulfanyl]-benzamideor a pharmaceutically acceptable salt thereof.
 7. A medicamentcomprising a VEGFR inhibitor for use in combination with an antagonistof a Programmed Death 1 protein (PD-1) for treating a cancer in anindividual, wherein the VEGFR inhibitor isN-methyl-2-[3-((E)-2-pyridin-2-yl-vinyl)-1H-indazol-6-ylsulfanyl]-benzamideor a pharmaceutically acceptable salt thereof, and further wherein thePD-1 antagonist is an anti-PD-1 monoclonal antibody which comprises aheavy chain and a light chain, wherein the heavy and light chainscomprise SEQ ID NO:21 and SEQ ID NO:22.
 8. The medicament of claim 6 or7, wherein the individual is a human.
 9. The medicament of any of claims6 to 8, wherein the cancer is a solid tumor that tests positive forPD-L1 expression by an immunohistochemical (IHC) assay.
 10. Themedicament of any of claims 6 to 8, wherein the cancer is renal cellcarcinoma.
 11. The medicament of any of claims 6 to 10, wherein the PD-1antagonist is MK-3475 and the VEGFR inhibitor is axitinib.
 12. Themedicament of claim 11, wherein the MK-3475 is formulated as a liquidmedicament which comprises 25 mg/ml MK-3475, 7% (w/v) sucrose, 0.02%(w/v) polysorbate 80 in 10 mM histidine buffer pH 5.5 and axitinib isformulated as a 1 mg tablet or a 5 mg tablet.
 13. A kit which comprisesa first container, a second container and a package insert, wherein thefirst container comprises at least one dose of a medicament comprisingan antagonist of a Programmed Death 1 protein (PD-1), the secondcontainer comprises at least one dose of a medicament comprising a VEGFRinhibitor, and the package insert comprises instructions for treating anindividual for cancer using the medicaments, wherein the PD-1 antagonistis an anti-PD-1 monoclonal antibody which comprises a heavy chain and alight chain, wherein the heavy and light chains comprise SEQ ID NO:21and SEQ ID NO:22, respectively, and further wherein the VEGFR inhibitorisN-methyl-2-[3-((E)-2-pyridin-2-yl-vinyl)-1H-indazol-6-ylsulfanyl]-benzamideor a pharmaceutically acceptable salt thereof.
 14. The kit of claim 13,wherein the instructions state that the medicaments are intended for usein treating an individual having a cancer that tests positive for PD-L1expression by an immunohistochemical (IHC) assay.
 15. The kit of claim13 or 14, wherein the individual is a human.
 16. The kit of any ofclaims 13 to 15, wherein the PD-1 antagonist is MK-3475 formulated as aliquid medicament and the VEGFR inhibitor is axitinib formulated as a 1mg tablet or a 5 mg tablet.
 17. The method, use or kit of any of claims1-3, 5-9, or 11-15, wherein the cancer is bladder cancer, breast cancer,clear cell kidney cancer, head/neck squamous cell carcinoma, lungsquamous cell carcinoma, malignant melanoma, non-small-cell lung cancer(NSCLC), ovarian cancer, pancreatic cancer, prostate cancer, renal cellcancer, small-cell lung cancer (SCLC), triple negative breast cancer,acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML),chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML),diffuse large B-cell lymphoma (DLBCL), follicular lymphoma, Hodgkin'slymphoma (HL), mantle cell lymphoma (MCL), multiple myeloma (MM),myeloid cell leukemia-1 protein (Mcl-1), myelodysplastic syndrome (MDS),non-Hodgkin's lymphoma (NHL), or small lymphocytic lymphoma (SLL). 18.The method, use or kit of any of the above claims, wherein the cancer isadvanced renal cell carcinoma.
 19. A method for treating a humanindividual diagnosed with a cancer, comprising administering to theindividual a combination therapy which comprises MK-3475 and axitinib,wherein (a) axitinib is administered at a dose of 5 mg BID and MK-3475is administered at a dose selected from the group consisting of 1 mg/kgQ3W, 2 mg/kg Q3W and 200 mg Q3W or (b) axitinib is administered at adose of 3 mg BID and MK-3475 is administered at a dose selected from thegroup consisting of 1 mg/kg Q3W, 2 mg/kg Q3W and 200 mg Q3W.
 20. Amedicament comprising: (a) MK-3475 for use in combination with axitinibfor treating a cancer in a human individual by a method comprisingadministering to the individual (i) axitinib at a dose of 5 mg BID andMK-3475 at a dose selected from the group consisting of 1 mg/kg Q3W, 2mg/kg Q3W and 200 mg Q3W or (ii) axitinib at a dose of 3 mg BID andMK-3475 at a dose selected from the group consisting of 1 mg/kg Q3W, 2mg/kg Q3W and 200 mg Q3W; or (b) axitinib for use in combination withMK-3475 for treating a cancer in a human individual by a methodcomprising administering to the individual (a) axitinib at a dose of 5mg BID and MK-3475 at a dose selected from the group consisting of 1mg/kg Q3W, 2 mg/kg Q3W and 200 mg Q3W or (b) axitinib at a dose of 3 mgBID and MK-3475 at a dose selected from the group consisting of 1 mg/kgQ3W, 2 mg/kg Q3W and 200 mg Q3W.